Oxytocin receptor antagonists have been found to be useful as tocolytic agents. Various oxytocin antagonists have been studied and implemented in the management of conditions such as preterm labor, dysmenorrhea and stopping labor prior to cesarean delivery.
A number of piperazinylcamphorsulfonyl oxytocin receptor antagonists, pharmaceutically acceptable salts thereof, and their use in treating preterm labor, dysmenorrhea and stopping labor prior to cesarean delivery are described in EP Patent Publication No. 532,097, published Mar. 17, 1993. In particular, the compound disclosed in Example 36 of EP 532,097, i.e., 1-((7,7-Dimethyl-2-endo-(2S-amino-4-(methylsulfonyl)butyramido)-bicyclo(2. 2.1)-heptan-1-yl)methanesulfonyl)-4-(2-methylphenyl)piperazine, has been found to be an effective inhibitor-of uterine activity and will hereafter be referred to as Compound A. ##STR3##
In certain farm animals (e.g., sheep, cattle, swine and goats) the beginning of the estrous cycle is typically marked by behavioral estrus when the female animal accepts the male for mating. Ovulation of the ovarian follicle occurs shortly after onset of estrus and cells in the follicle give rise to the corpus luteum. The cells that form the corpus luteum produce progesterone and they also produce oxytocin. The secretion of oxytocin from the corpus luteum and/or pituitary acts on the uterine endometrium to stimulate the secretion of prostaglandins (in particular PGF) which, in ram, causes the regression of the corpus luteum of the ovary. PGF is, therefore, the luteolytic hormone. In the cycling animal (i.e., where mating and fertilization have not occurred), destruction of the corpus luteum removes the source of progesterone which is key to the preparation of the uterus for pregnancy.
The presence of a viable conceptus (i.e., the embryo and its associated membranes) is necessary to prevent the luteolytic process. In fact, the first key signal that the conceptus must produce is the one to prevent regression of the corpus luteum (i.e., the mammal recognition of pregnancy signal). Thus, in the animal where mating and fertilization have occurred, the conceptus secretes a factor that antagonizes the action of oxytocin to induce luteolysis. This results in maintenance of a functioning corpus luteum and the continued secretion of progesterone which is obligatory to the initiation of pregnancy.
Early embryonic loss is a major cause of infertility in farm animals resulting in considerable economic costs. Embryonic deaths claim 30 to 50% of embryos in domestic livestock. Most of this embryonic death loss occurs just prior to or during the period of maternal recognition of pregnancy. Many of the conceptuses are slightly retarded in their development and either do not produce the maternal recognition signal at the appropriate time or do not produce it in adequate amounts. Consequently, leuteolysis is not inhibited and the corpus luteum regresses, resulting in early embryonic loss.
It has now been found that administration of an oxytocin antagonist of the present invention at this critical period after fertilization (i.e., just prior to or during the period of maternal recognition of pregnancy) supplements the natural signal from the conceptus (i.e., maternal recognition of pregnancy) to prolong corpus luteal function. The result is to increase pregnancy rates by enhancing the chances of impregnation through a reduction in embryonic loss.
In addition to the infertility problem caused by embryonic loss in livestock, neonatal morbidity and mortality also result in considerable expense and economic loss to farmers. Approximately 80% of livestock are delivered at night and up to 5 to 10% of newborns die because the deliveries are not monitored properly. Thus, a method of controlling the timing of parturition in livestock to ensure monitoring of the neonates would be highly beneficial, resulting in increased survival rates.
It has now been discovered that oxytocin antagonists of the present invention can be used in livestock to control the timing and delivery of neonates to the daytime, thereby allowing for monitoring of the neonates and enhanced survival rates.
Additionally, synchronization of estrus among a group of farm animals would increase the ease and efficiency of farm management resulting in savings of both time and cost. For example, the synchronization of estrus among a herd of cows would allow for mating or artificial insemination of the entire herd on the same day. Moreover, by fertilizing the entire herd on the same day, the cows would all be expected to deliver the neonates on or about the same day. Thus, a farmer would realize time and cost savings during breeding and the resulting births by synchronizing estrus of the entire herd.
It has now been found that administration of an oxytocin antagonist of the instant invention can be used to control the timing of estrus in a cycling animal by preventing luteal regression; by using an oxytocin antagonist to prevent luteal regression and delay estrus, a farmer will be able to synchronize estrus among a group of farm animals, thereby easing farm management.